1. Field of the Invention
The present invention relates to novel compounds, pharmaceutical compositions containing them, methods for preparing the compounds and their use as medicaments. More specifically, compounds of the invention can be utilized in the treatment of conditions mediated by nuclear receptors, in particular the Retinoid X Receptor (RXR) and the Peroxisome Proliferator-Activated Receptor (PPAR) families. The compounds of the invention can also be used in combination with ligands for other nuclear receptors which are known to form dimeric complexes with RXR receptors, for example the Peroxisome Proliferator-Activated Receptor (PPAR) family.
2. Description of the Related Art
Non-insulin dependant diabetes mellitus (NIDDM, Type II diabetes) is a condition characterized by abnormal and ineffective insulin action and secretion. The entry of glucose from the blood into the cells of liver, skeletal muscle and adipose tissue is promoted by insulin action.
In the diabetic, tissues dependant on insulin are unable to assimilate glucose normally (insulin resistance), the result being an accumulation of glucose within the blood (hyperglycemia). Type II diabetes typically afflicts people over 40, and obesity is often a contributing factor. Regulation of diet and exercise can reduce to some extent the problems associated with NIDDM, but commonly insulin therapy or other oral hypoglycemic agents are the treatments of choice.
In addition to the range of insulin formulations, the most widely used hypoglycemic agents to date are sulphonylureas but in respective cases potentially fatal hyperinsulinemia or hypoglycemia can develop, and additional problems involving the cardiovascular, renal, neural and visual systems can also ensue.
More recently, a class of compounds termed thiazolidinediones (e.g., ciglitazone, pioglitazone, englitazone, troglitazone and BRL 49653) have been shown to reduce hyperglycemia by promoting insulin action without additional insulin secretion, and without causing undesirable hypoglycemia, even at elevated doses. Their effect is proposed to be a result of agonism at the PPAR receptor.
Even more recently, it has been reported that RXR agonists such as LGD 1069 and LG 100268 activate RXR/PPAR heterodimers, causing reduction in glucose, insulin and triglyceride levels in ob/ob and db/db mice (Mukherjee et al., Nature 1997, 386, 407410, Heyman and Mukherjee WO 97/10819). This effect is due to activation at the RXR part of the heterodimer. In turn these RXR/PPAR heterodimers can also be activated by PPAR agonists (e.g., thiazolidinediones) to give a similar effect, and it has been shown that at submaximal levels of either the RXR or PPAR agonist, addition of the complimentary agonist provides an additive and possibly synergistic response, and results in enhanced transcription and subsequently additional lowering of hyperglycemia, hyperinsulinemia and hypertriglyceridemia. It has therefore been proposed that compounds acting as agonists at both the RXR and PPAR receptors can be used as insulin sensitizers for the treatment of Type II diabetes and related symptoms.
Coronary artery disease (CAD) is the major cause of death in Type 2 diabetic and metabolic syndrome patients (i.e., patients that fall within the `deadly quartet` category of impaired glucose tolerance, insulin resistance, hypertriglyceridemia and/or obesity).
The hypolipidemic fibrates and antidiabetic thiazolidinediones separately display moderately effective triglyceride-lowering activities although they are neither potent nor efficacious enough to be a single therapy of choice for the dyslipidemia often observed in Type 2 diabetic or metabolic syndrome patients. The thiazolidinediones also potently lower circulating glucose levels of Type 2 diabetic animal models and humans. However, the fibrate class of compounds are without beneficial effects on glycemia. Studies on the molecular actions of these compounds indicate that thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased and decreased expression of specific enzymes and apolipoproteins respectively, both key players in regulation of plasma triglyceride content. Fibrates, on the one hand, are PPAR.alpha. activators, acting primarily in the liver. Thiazolidinediones, on the other hand, are high affinity ligands for PPAR.gamma. acting primarily on adipose tissue.
Adipose tissue plays a central role in lipid homeostasis and the maintenance of energy balance in vertebrates. Adipocytes store energy in the form of triglycerides during periods of nutritional affluence and release it in the form of free fatty acids at times of nutritional deprivation. The development of white adipose tissue is the result of a continuous differentiation process throughout life. Much evidence points to the central role of PPAR.gamma. activation in initiating and regulating this cell differentiation. Several highly specialized proteins are induced during adipocyte differentiation, most of them being involved in lipid storage and metabolism. The exact link from activation of PPAR.gamma. to changes in glucose metabolism, most notably a decrease in insulin resistance in muscle, has not yet been clarified. A possible link is via free fatty acids such that activation of PPAR.gamma. induces Lipoprotein Lipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoA Synthetase (ACS) in adipose tissue but not in muscle tissue. This, in turn, reduces the concentration of free fatty acids in plasma dramatically, and due to substrate competition at the cellular level, skeletal muscle and other tissues with high metabolic rates eventually switch from fatty acid oxidation to glucose oxidation with decreased insulin resistance as a consequence.
PPAR.alpha. is involved in stimulating .beta.-oxidation of fatty acids. In rodents, a PPAR.alpha.-mediated change in the expression of genes involved in fatty acid metabolism lies at the basis of the phenomenon of peroxisome proliferation, a pleiotropic cellular response, mainly limited to liver and kidney and which can lead to hepatocarcinogenesis in rodents. The phenomenon of peroxisome proliferation is not seen in man. In addition to its role in peroxisome proliferation in rodents, PPAR.alpha. is also involved in the control of HDL cholesterol levels in rodents and humans. This effect is, at least partially, based on a PPAR.alpha.-mediated transcriptional regulation of the major HDL apolipoproteins, apo A-I and apo A-II. The hypotriglyceridemic action of fibrates and fatty acids also involves PPAR.alpha. and can be summarized as follows: (I) an increased lipolysis and clearance of remnant particles, due to changes in lipoprotein lipase and apo C-III levels, (II) a stimulation of cellular fatty acid uptake and their subsequent conversion to acyl-CoA derivatives by the induction of fatty acid binding protein and acyl-CoA synthase, (III) an induction of fatty acid-oxidation pathways, (IV) a reduction in fatty acid and triglyceride synthesis, and finally (V) a decrease in VLDL production. Hence, both enhanced catabolism of triglyceride-rich particles as well as reduced secretion of VLDL particles constitutes mechanisms that contribute to the hypolipidemic effect of fibrates.
A number of compounds have been reported to be useful in the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia (U.S. Pat. No. 5,306,726, PCT Publications nos. WO91/19702, WO 95/03038, WO 96104260, WO 94/13650, WO 94/01420, WO 97/36579, WO 97/25042, WO 95/17394, WO 99108501, WO 99/19313 and WO 99/16758).